Thiophene and bioisostere derivatives as new MMP12 inhibitors

Bioorganic & Medicinal Chemistry Letters 21 (2011) 528–530

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Thiophene and bioisostere derivatives as new MMP12 inhibitors Matthew Badland b,⇑, Delphine Compère a,⇑, Karine Courté a, Anne-Claude Dublanchet a, Stéphane Blais a, Ajith Manage b, Guillaume Peron b, Roger Wrigglesworth a a b

Pfizer Global Research and Development, Fresnes Laboratories, 3–9 Rue de la Loge, F-94265 Fresnes Cedex, France Evotec OAI, 151 Milton Park, Abingdon, Oxon OX14 SD, UK

a r t i c l e

i n f o

Article history: Received 28 September 2010 Revised 15 October 2010 Accepted 16 October 2010 Available online 9 November 2010

a b s t r a c t A new MMP12 inhibitor series has been identified containing a thiophene moiety. Different approaches have been considered to replace this potential toxicophore. a-Fluorothiophene derivatives were the most interesting compounds. Their synthesis is presented. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: MMP12 inhibitor series Thiophene moiety a-Fluorothiophene derivatives Isothiazole

Since MMP12 has been shown to play an important role in tissue destruction as well as in macrophage recruitment in the lungs following cigarette smoking, this enzyme has become an attractive target for COPD (Chronic Obstructive Pulmonary Disease).1 The original hit 1 characterized by a 4-phenylthiophene-2carboxamide structure was identified in HTS with a moderate potency (13 lM). The key strategy consists in identifying MMP12 inhibitors which bind to the S10 pocket and do not interact with the enzyme on its catalytic domain unlike zinc chelators. This should ensure a good selectivity profile against other MMPs structurally close to MMP12 (MMP13, 2, 3) and minimize the classical side effects observed with other MMPs inhibitors. A full analoging program has been developed around this hit.2 In particular in this paper, synthetic efforts have been focused on replacement of the central thiophene core or on substitution of the reactive position a to the sulfur atom. Non fused thiophene is considered a potential toxicophore3 leading to toxicity particularly hepatotoxicity, immunotoxicity and nephrotoxicity.4 Removal of some of the thiophene containing therapeutic agents from use due to hepatoxicities has led to an increased effort in understanding the cause of these toxic events. The metabolism of thiophenes is principally mediated by cytochrome P450. Thiophenes undergo hydroxylation at the carbon atoms adjacent to the sulfur atom and are converted to 2 or 5-hydroxythiophenes as described in the well documented article related to fivemembered aromatic ring biotransformation reactions by Dalvie

et al.3a However, modifications to this substructure could mitigate or avoid toxicity by introduction of bioisosteres, 2,5-substitution on the thiophene, or ring deactivation by addition of adjacent functionality.5 In this context, we report herein the synthesis and biological evaluation of isothiazole core structures A and B and fluorothiophene derivatives C where the thiophene reactive position has been blocked with a fluorine atom (Fig. 2). The preparation of methyl 4-(4-bromophenyl)-5-fluorothiophene carboxylate E is described. This versatile template, as well as the isothiazole core analog D, lead to the synthesis of elaborated targeted compounds potentially inhibiting MMP12. The concept of bioisosterism has been widely utilized as one strategy for lead optimization in the discovery of new drugs.6 The bioisostere approach has been shown to be useful to augment potency or to modify certain physiological properties of a lead compound. The isosteric replacement of the thiophene moiety was motivated here to avoid a potential toxicophore and to increase future confidence in this promising series. Isothiazole core structure A has been identified as a bioisostere of the thiophene

MeO

H N

N O

S O

⇑ Corresponding authors. E-mail address: matthew.badland@pfizer.com (M. Badland). 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.10.087

Figure 1. Compound 1, initial hit identified from a mass screen of MMP12 catalytic domain.

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M. Badland et al. / Bioorg. Med. Chem. Lett. 21 (2011) 528–530 R1

R1 H N R2

N

S

S

a

R1 H N

R2

F

N O

H N R2

CN

S

F

Route 1

CN

S

S

O

A

O2N

O

B

b

C

Br

Br

Figure 2. Isothiazole core structures A and B and a-fluorothiophene C.

c (H, OMe) S

Br

S

O

O

D

E

Figure 3. General templates leading to potential MMP12 inhibitors.

H2N

Br

Br a, b

c, d

.HCl

S

N

N

F3CO

O

F3CO

O OH

g, h

e, f OH N

O

S

S

N

S

H N

S N

O

O

Scheme 2. Reagents and conditions: Route 1 (a) KF, PPh4Br, phtaloyldichloride, sulfolane; (b) Br2, 10 h at 5 °C; Route 2 (c) with aldehyde as starting material: Selectfluor™ in CH3CN/H2O, five days at 70 °C, 90% conversion HPLC; with methyl ester as starting material: Selectfluor™ in CH3CN, five days until 70 °C, 30% conversion HPLC and degradation.

O F

S

S C'

O

N

Route 2

O

Br

5

(H, OMe) F

O

Scheme 1. Reagents and conditions: (a) NaOH, TBME; (b) HNO3, NaNO2 in H3PO4 then CuBr–HBr; (c) CrO3, H2SO4; (d) H2SO4, MeOH; (e) 4-trifluoromethoxyphenylboronic acid, Pd(PPh3)4, K3PO4 aq 2 M, DME, 80 °C; (f) LiOH, MeOH/H2O; (g) trans 4-amino methyl-cycloxanecarboxylic acid ethyl ester, HATU, DIPEA, DMF; (h) LiOH, EtOH/H2O.

ring and has been prepared according to the literature procedure.7 The general template D described in Figure 3 has been made via a similar route to that of the original lead, Figure 1, with the inclusion of the bromo-phenyl ring for subsequent Suzuki coupling and the introduction of diversity. Conversely, isomer isothiazoles B are less common as five-membered heteroaromatic bioisosteric rings in drugs and no preparation has been reported in the last few decades. The chemistry of the isothiazole derivative B, from which first close analogous were prepared in 1959,8 has been performed from commercially available 5-amino-3-methylisothiazole (Scheme 1). As anticipated in the original paper with 3-methylisothiazole, the bottleneck was the oxidation of the methyl group due to its relatively inert character (13% yield for step c). We nevertheless obtained several grams of the scaffold intermediate B0 leading to the expected compound 4. In the field of bioisosteric chemistry, our effort was directed to the development of fluorothiophenes where the reactive position adjacent to sulfur atom is blocked with a fluorine atom. Very few viable synthetic routes exist for the synthesis of the 4-bromo-5fluorothiophene-2-carbonyl template C0 especially if we exclude use of hazardous gases like perchloryl fluoride (FClO3).9 Our first approach consisted in the construction of this elaborate thiophene moiety with a fluorine atom as reactive position blocker and bromine in position 4 for the following Suzuki coupling steps. In our initial trials, we had expected to obtain derivative C0 via a fluorodenitration reaction10 followed by a regioselective bromination (Scheme 2, Route 1).11 Such a route was difficult to perform due to the loss of volatile compound 5-fluorothiophene-2-carbonitrile

and issues of reproducibility on larger scale. The alternative route we considered was made use of the reagent Selectfluor™ (so called F-TEDA-BF4), a convenient source of F+, which is commercially available and with the advantage to be relatively stable and easy to handle.12 To our knowledge, electrophilic fluorinating agents (Selectfluor™ and analogous derivatives) have been previously used on a position of thiophene ring but with low yields.13 In our conditions, the reaction was incomplete even if the conversion was satisfactory in the case of 4-bromothiophene carbaldehyde (90% conversion monitored by HPLC). Unfortunately it was impossible to isolate fluorothiophene derivative C0 from starting material using classical separation conditions. As a second approach, we decided to start from a scaffold already bearing R1 as a substituent (Scheme 3).14 Balz-Schiemann reaction failed in our conditions (Route 1, step b). Indeed literature references can be found where these conditions were successful on thiophene moiety in position 3 or 415 but not in the position adjacent to sulfur atom.16 It is presumably related to a stability issue of a-aminothiophene17 even though we did not observe it with our substrate. We were successful in identifying Selectfluor™ as a good alternative in this case (Route 2) where the separation of the nonfluoronated starting material is carried out as the last step using reverse phase chromatography (10% yield for steps c and d). Table 1 shows the activity of the different bioisosteric replacements of thiophene ring. Fluorothiophene 5 appears to show promising activity when compared to the parent compound 1. Encouraged by this result, we were interested in providing a general method to access the a-fluorothiophene ring. The approach using Selectfluor™ has been extended to compounds such as E0 leading to E (Scheme 4), which is a key template in our program. One equivalent of the reagent provided 60% conversion the desired compound but contaminated by starting material. Purification on silica gel in isocratic conditions R1

R1

R1

a

b

O O2N

O H2N

S O

O F

S O

Route 1

R1

S O

R1 c, d, e, f

H N

O F

S O

R1 =

OCF3

R2

S O

Route 2 5

R2 =

CO2H

Scheme 3. Reagents and conditions: Route 1 (a) H2, Pd/C 10% in MeOH; (b) NaNO2, HBF4 0 °C then heating: obtention of reduced compound; Route 2 (c) Selectfluor™, 3 h at 50 °C in CH3CN, 50% conversion HPLC; (d) LiOH in EtOH/H2O; (e) trans 4(aminomethyl)cycloxanecarboxylic acid ethyl ester or 4-(trifluoromethoxy)aniline, HATU, DIPEA, DMF; (f) LiOH, EtOH/H2O.

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Table 1 In vitro profile of bioisosteric replacement of thiophene moiety F3CO

O OH H N S O

Compd

IC50a (lM) MMP12

Core structure variation

0.40

2 S

3.6

3 N

ranges (Table 2). Their synthesis is based on versatile palladiumcatalyzed coupling chemistry followed by a peptidic coupling sequence as previously demonstrated2 and shown in Scheme 3 (Route 2). In summary, we have developed a strategy to access a-fluorothiophene derivatives as new MMP12 inhibitors. Even though in our studies no evidence of toxicity related to the thiophene structure has been detected (Ames Biolum and Reactive Metabolites negative) so far, based on previous reports3 we consider the present series potentially less toxicophoric. Besides having blocked the reactive position of the thiophene moiety, we have also moderately increased the activity when comparing compound 5 to the non fluoro derivative 1 (Fig. 1). Acknowledgements

S

The authors would like to thank Dr. Claude Wakselman and Dr. Emmanuel Magnier for helpful advice in fluorine chemistry.

31

4 S N

References and notes 5

0.14 F

a

S

Values IC50 of MMP12 catalytic domain.

Br

Br

a O

O F

S

S

O

O

E0

E

Scheme 4. (a) Selectfluor overnight at 70 °C, 60% conversion HPLC.

Table 2 In vitro profile of a-fluorothiophene R1 H N R2

F

S O

R

1

2

IC50 (lM) MMP12

R OCF3

CO2H

0.20

CONH2

0.085

Ph OCF3 Ph O

CO2H

0.007

O CO2H

0.024

CO2H

0.013

Ph

N Ph

(heptane/dichloromethane: 1/1) provided the pure derivative E with a 40% yield. More than ten grams of intermediate E has been produced by this method. This synthetic strategy has been successfully applied to the preparation of various MMP12 inhibitors with nanomalor activity

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